Robert R. Muder

Antibiotic therapy for Pseudomonas aeruginosa bacteremia: Outcome correlations in a prospective study of 200 patients*

PURPOSE AND PATIENTS AND METHODS We performed a prospective clinical study of 200 consecutive patients with Pseudomonas aeruginosa bacteremias to analyze in vitro susceptibility and synergistic testing of antibiotics the patients received and clinical parameters to assess their relationship to survival. RESULTS No significant correlation between in vitro susceptibility testing (minimal inhibitory concentrations/minimal bactericidal concentrations) and outcome could be demonstrated. Similarly, improved outcome could not be demonstrated for patients receiving antibiotic combinations that were synergistic in vitro (either time-kill or checker-board) versus those combinations that were not. There was also no correlation between results obtained by time-kill curve and checkerboard synergistic testing, i.e., combinations found to be synergistic by one method were not necessarily synergistic by the other method. Clinical parameters associated with improved survival were a urinary portal of entry and absence of neutropenia. Conversely, survival was significantly decreased when the portal was the respiratory tract. The mortality rate between patients receiving combination therapy (27%) and monotherapy (47%) was significant (p less than 0.02); this significant relationship held true for most subgroups including malignancy, nosocomial infection, and infection site. CONCLUSION Increasing effort should be placed on ensuring timely administration of combination therapy to patients with P. aeruginosa bacteremia since the use of combination therapy was even more important in determining outcome than was underlying disease.

Methicillin-Resistant Staphylococcal Colonization and Infection in a Long-Term Care Facility

OBJECTIVE To determine the natural history of colonization by methicillin-resistant Staphylococcus aureus (MRSA) among patients in a long-term care facility. We specifically sought to determine if MRSA colonization was predictive of subsequent infection. DESIGN Cohort study. SETTING Long-term Veterans Affairs Medical Center. PATIENTS A total of 197 patients residing on two units were followed with regular surveillance cultures of the anterior nares. MAIN OUTCOME MEASUREMENT The development of staphylococcal infection. RESULTS Thirty-two patients were persistent carriers of MRSA and 44 were persistent carriers of methicillin-susceptible strains (MSSA). Twenty-five percent of MRSA carriers had an episode of staphylococcal infection compared with 4% of MSSA carriers and 4.5% of non-carriers (P less than 0.01; relative risk 3.8; 95% CI, 2.0 to 6.4). The rate of development of infection among MRSA carriers was 15% for every 100 days of carriage. Using logistic regression analysis, persistent MRSA carriage was the most significant predictor of infection (P less than 0.001; odds ratio, 3.7). Seventy-three percent of all MRSA infections occurred among MRSA carriers. Isolates of MRSA from 7 patients were typed. Colonizing and infecting strains had the same phage type in all 7 patients and the same pattern of plasmid EcoRI restriction endonuclease fragments in 5 patients. CONCLUSIONS Colonization of the anterior nares by MRSA predicts the development of staphylococcal infection in long-term care patients; most infections arise from endogenously carried strains. Colonization by MRSA indicates a significantly greater risk for infection than does colonization by MSSA. The results offer a theoretic rationale for reduction in MRSA infections by interventions aimed at eliminating the carrier state.

Determinants of Vancomycin Resistance and Mortality Rates in Enterococcal Bacteremia: A Prospective Multicenter Study

Enterococcus species have become increasingly prominent as etiologic agents of nosocomial bacteremia (19). Enterococcal bacteremia has a mortality rate of 42% to 73% (10, 11) and is common among debilitated patients and those with severe underlying illnesses (5, 6, 1217). Enterococci have low-level resistance to penicillins, aminoglycosides, and clindamycin and are intrinsically resistant to cephalosporins. Enterococci may acquire resistance to additional antibiotics, including -lactams, aminoglycosides, and glycopeptides (18). Resistance to multiple antibiotics, in particular vancomycin coupled with high-level ampicillin and aminoglycoside, has been reported with increasing frequency (19). At present, more than 20% of enterococci isolated from intensive care units exhibit vancomycin resistance. The addition of vancomycin resistance to high-level ampicillin and aminoglycoside resistance limits available therapeutic options (20). To investigate the clinical implications of antibiotic resistance in enterococci, we instituted a prospective, multicenter observational study of outcome in patients with enterococcal bacteremia. We sought to determine 1) factors associated with infection with vancomycin-resistant enterococci [VRE], 2) factors predictive of death in patients with enterococcal bacteremia, 3) the effect of vancomycin resistance on mortality rates, and 4) the effect of antibiotic therapy on outcome. Methods All patients with enterococcal bacteremia were hospitalized at the University of Pittsburgh Medical Center and the Veterans Affairs (VA) Medical Center (Pittsburgh, Pennsylvania), Detroit Medical Center and John D. Dingell VA Medical Center (Detroit, Michigan), Rush-Presbyterian-St. Lukes Medical Center (Chicago, Illinois), New England Medical Center (Boston, Massachusetts), and William Beaumont Hospital (Royal Oak, Michigan). Clinical data were obtained from review of medical records. The institutional review boards of four participating institutions approved the study. At the fifth institution, the study was considered exempt from review because it involved confidential use of existing records and bacterial isolates. Microbiology Blood for culture was obtained by venipuncture or through central venous catheters. Enterococcal species were determined by using either VITEK (bioMerieux Vitek, Inc., Hazelwood, Missouri) or MicroScan (MicroScan, Inc., West Sacramento, California) systems according to the manufacturers recommendations. Identification of species other than E. faecalis and E. faecium was confirmed as reported elsewhere (21). One of the authors standardized antimicrobial susceptibilities by using Etest strips (AB BIODISK North America, Inc., Piscataway, New Jersey). Enterococcus faecium isolates showing resistance or intermediate susceptibility to quinupristindalfopristin were tested by broth microdilution and disk diffusion to confirm reduced susceptibility. If the isolate was unavailable, antimicrobial susceptibilities reported by the submitting microbiology laboratories were used. Minimum inhibitory concentration (MIC) breakpoints from the Ninth National Committee for Clinical Laboratory Standards (NCCLS) were used (22). Because imipenem MIC values for enterococci are not defined, NCCLS breakpoints for Enterobacteriaceae were used (22). Quality control was monitored by using E. faecalis American Type Culture Collection (ATCC) 29212. Nine enterococcal isolates displayed intermediate susceptibility to vancomycin (MIC, 8 to 16 g/mL) but were considered resistant for the purposes of analysis. Vancomycin resistance genotypes of selected clinical isolates were determined by using polymerase chain reaction (PCR) amplification with primers specific for intragenic sequences of the vanA and vanB genes (23, 24). Control strains included vancomycin-susceptible E. faecalis ATCC 29212, E. faecium BM4147 (vanA) (25), and E. faecalis V583 (vanB) (26). For determination of aminoglycoside resistance genes, genomic DNA for PCR amplification was prepared with the InstaGene Matrix kit (BioRad Laboratories, Hercules, California) and PCR performed as reported elsewhere (27). Aminoglycoside resistance genes detected included aac(6)-Ie-aph(2)-Ia (28), aph(2)-Ic (29), aph(2)-Id (30), and aph(2)-Ib (31). Definitions Clinically significant bacteremia was defined as isolation of enterococci in two or more separately obtained blood cultures or from a single blood culture and from a concomitant site of infection in a clinical scenario compatible with bacteremic infection (6). Endocarditis was defined by using the Duke criteria (32). Polymicrobial bacteremia was defined as isolation from blood culture of one or more additional species of bacteria concomitantly with enterococci (same blood culture or another blood culture within 24 hours of the initial blood culture yielding enterococci). A single concomitant isolation of another bacterial species was sufficient, except for isolation of coagulase-negative staphylococci, diphtheroids, -hemolytic streptococci, and Bacillus species that required isolation from two blood cultures. Length of hospitalization was defined as the time in days from hospital admission to development of clinically significant enterococcal bacteremia. Enterococcal bacteremia occurring 60 days or more from a previous episode in patients already enrolled was counted as a separate episode. The end point was survival at 14 days from the first positive blood culture. Patients discharged from the hospital before 14 days were considered survivors. Medical records were reviewed at entry, at 2 weeks, at 4 weeks, and at 6 weeks (or at time of discharge or death if earlier than 6 weeks). We collected information on patient demographic characteristics, underlying disease, Acute Physiology and Chronic Health Evaluation (APACHE) II scores at bacteremia onset, antibiotic use, use of glucocorticosteroids and other immunosuppressive drugs, and receipt of invasive devices and procedures in the 2 weeks before bacteremia onset. Antibiotic therapy during the 6 weeks after the onset of bacteremia was recorded. Beyond 6 weeks, patients were followed for evidence of relapse of bacteremia and for survival to discharge or death. Immunosuppressive drugs included cyclosporine, cyclophosphamide, azathioprine, tacrolimus, methotrexate, and cytotoxic chemotherapy. Appropriate antibiotic therapy was defined as treatment with at least one antibiotic that had in vitro activity (as defined by Etest) against the enterococcal isolate, initiated within 48 hours of the initial positive enterococcal blood culture and continuing for at least 72 hours. Antibiotics considered potentially active included penicillin, ampicillin, ureidopenicillin, vancomycin, quinupristindalfopristin, chloramphenicol, doxycycline, and rifampin. Statistical Analysis For categorical variables, proportions were compared by using the Fisher exact test. Continuous variables were analyzed with the MannWhitney rank-sum test. Multivariate analysis was done by using logistic regression. Variables with a two-tailed P value of 0.05 were included in stepwise logistic regression models for vancomycin resistance and 14-day mortality. The initial bacteremic episode for each patient (n = 398) was used for the evaluation of risk factors for bacteremia caused by VRE. Patients who were alive 14 days after the onset of enterococcal bacteremia (n = 321) were evaluated for factors associated with microbiological failure. Statistical analysis of the data was performed by using the Prophet system (MarketMiner, Inc., Charlottesville, Virginia) and Epistat (Epistat Services, Richardson, Texas). Results Enterococcal Bacteremia We studied hospitalized patients 16 years of age or older with clinically significant hospital- or community-acquired enterococcal bacteremia. From February 1995 through March 1997, 391 consecutive patients from five participating institutions were entered into the study. An additional 9 patients from Pittsburgh were entered into the study over a 6-month period (October 1998 through March 1999) to increase the total number of patients to 400. These patients were consecutive and unselected. Two patients younger than 16 years of age were excluded, leaving 398 patients for evaluation. Eighty-nine patients were from the University of Pittsburgh Medical Center and the VA Medical Center, 97 were from Rush-Presbyterian-St. Lukes Medical Center, 95 were from the Detroit Medical Center and John D. Dingell VA Medical Center, 61 were from New England Medical Center, and 56 were from the William Beaumont Hospital. Blood cultures yielded 398 enterococcal isolates. Of these, 60% (239 of 398) were E. faecalis and 37% (148 of 398) were E. faecium. Three percent (10 of 398) of the isolates belonged to the less common enterococcal species, which include E. avium, E. casseliflavus, E. durans, E. gallinarum, and E. raffinosus. The species of one isolate could not be identified. Seventeen recurrences were seen at 60 or more days after the initial bacteremia. Of these, 14 were caused by the same enterococcal species as the initial episode. In 12 of these 14 episodes, the pair of isolates had the same susceptibilities to vancomycin. Overall, 35% of the 398 enterococcal isolates were resistant to vancomycin (MIC 32 g/mL), 63% were susceptible to vancomycin (MIC 4 g/mL), and 2% displayed intermediate susceptibility (MIC, 8 to 16 g/mL). Table 1 shows the susceptibility patterns of the two major Enterococcus species. Eight percent of the E. faecalis isolates were resistant to vancomycin, 91% were susceptible, and 1% displayed intermediate susceptibility. In contrast, 80% of the E. faecium isolates were resistant to vancomycin, 18% were susceptible, and 2% displayed intermediate susceptibility. Of the 11 isolates of other species, none were resistant to vancomycin, 73% (8 of 11) were susceptible to vancomycin, and 27% (3 of 11) displayed intermediate susceptibility to vancomycin. Table 1. Pr

Pneumonia in residents of long-term care facilities: epidemiology, etiology, management, and prevention.

Pneumonia is a leading cause of morbidity and mortality among patients in long-term care facilities; the median reported incidence is 1 per 1,000 patient-days. Risk factors include functional dependency, chronic pulmonary disease, and conditions causing aspiration. The frequency of etiologic agents varies widely among reports; for example; Streptococcus pneumoniae ranges from 0% to 39% of cases, and gram negative bacilli ranges from 0% to 51% of reported cases. Viral respiratory infections, particularly influenza and respiratory syncytial virus, typically occur in outbreaks. Mortality varies from 5% to 40%; functional status is the major determinant of survival. Many patients receive inadequate initial evaluations, and as many as 40% receive no physician visit during the episode. Although transfer to an acute care facility occurs in 9% to 51% of cases, most transferred patients could be managed in the nursing home with minimal additional support. Appropriate evaluation includes examination by a practitioner, recording of vital signs, chest radiograph, and examination of an adequate sputum sample, if available. Patients without contraindications to oral therapy or severe abnormalities of vital signs (pulse > 120 beats per minute, respirations >30 per minute, systolic blood pressure < 90) may initially receive oral therapy. Appropriate oral agents include amoxicillin/clavulanate, second generation cephalosporins, quinolones active against S pneumoniae, or trimethoprim/sulfamethoxazole. Appropriate parenteral agents include beta-lactam/beta-lactamase inhibitor combinations, second or third generation cephalosporins, or quinolones. Pneumococcal and influenza vaccines should be administered to all residents. Future studies should focus on identifying risk factors for pneumonia that are amenable to intervention and to identifying highly effective, preferably oral, antimicrobial regimens in randomized trials.

Significance of isolation of aspergillus from the respiratory tract in diagnosis of invasive pulmonary aspergillosis. Results from a three-year prospective study

The isolation of Aspergillus species from respiratory secretions has been regarded as being of limited usefulness in the antemortem diagnosis of invasive pulmonary aspergillosis. One hundred and eight consecutive patients were evaluated in whom Aspergillus species were isolated from respiratory secretions. Invasive aspergillosis was not demonstrated in non-immunosuppressed patients or in patients with solid tumors in the absence of neutropenia. Lung tissue was examined in 17 patients with leukemia and/or neutropenia; all had invasive aspergillosis. Tissue examination was not performed in 20 neutropenic patients; of 17 not receiving antifungal therapy, 16 died. Multivariate statistical analysis showed that neutropenia and absence of cigarette smoking were significant predictors of invasive aspergillosis in patients with respiratory tract cultures yielding Aspergillus. All cases of invasive aspergillosis were associated with A. fumigatus or A. flavus. The isolation of A. fumigatus or A. flavus from the respiratory tract of a patient with leukemia and/or neutropenia is highly predictive of invasive infection. Empiric amphotericin B therapy, without the necessity for tissue diagnosis, should be considered in this patient subgroup.

Development of minimum criteria for the initiation of antibiotics in residents of long-term-care facilities: Results of a consensus conference

Establishing a clinical diagnosis of infection in residents of long-term-care facilities (LTCFs) is difficult. As a result, deciding when to initiate antibiotics can be particularly challenging. This article describes the establishment of minimum criteria for the initiation of antibiotics in residents of LTCFs. Experts in this area were invited to participate in a consensus conference. Using a modified delphi approach, a questionnaire and selected relevant articles were sent to participants who were asked to rank individual signs and symptoms with respect to their relative importance. Using the results of the weighting by participants, a modification of the nominal group process was used to achieve consensus. Criteria for initiating antibiotics for skin and soft-tissue infections, respiratory infections, urinary infections, and fever where the focus of infection is unknown were developed.

Infection Due to Legionella Species Other Than L. pneumophila

In addition to Legionella pneumophila, 19 Legionella species have been documented as human pathogens on the basis of their isolation from clinical material. Like L. pneumophila, other Legionella species are inhabitants of natural and man-made aqueous environments. The major clinical manifestation of infection due to Legionella species is pneumonia, although nonpneumonic legionellosis (Pontiac fever) and extrapulmonary infection may occur. The majority of confirmed infections involving non-pneumophila Legionella species have occurred in immunosuppressed patients. Definitive diagnosis requires culture on selective media. Fluoroquinolones and newer macrolides are effective therapy. A number of nosocomial cases have occurred in association with colonization of hospital water systems; elimination of Legionella species from such systems prevents their transmission to susceptible patients. It is likely that many cases of both community-acquired and nosocomial Legionella infection remain undiagnosed. Application of appropriate culture methodology to the etiologic diagnosis of pneumonia is needed to further define the role of these organisms in disease in humans.

The economic burden of Clostridium difficile

Although Clostridium difficile (C. difficile) is the leading cause of infectious diarrhoea in hospitalized patients, the economic burden of this major nosocomial pathogen for hospitals, third-party payers and society remains unclear. We developed an economic computer simulation model to determine the costs attributable to healthcare-acquired C. difficile infection (CDI) from the hospital, third-party payer and societal perspectives. Sensitivity analyses explored the effects of varying the cost of hospitalization, C. difficile-attributable length of stay, and the probability of initial and secondary recurrences. The median cost of a case ranged from

Association between the Presence of Enterococcal Virulence Factors Gelatinase, Hemolysin, and Enterococcal Surface Protein and Mortality among Patients with Bacteremia Due to Enterococcus faecalis

9179 to

Isolation of Staphylococcus aureus from the Urinary Tract: Association of Isolation with Symptomatic Urinary Tract Infection and Subsequent Staphylococcal Bacteremia

11 456 from the hospital perspective,